Cell line of lymphocytes comprising gamma-delta t cells, composition and production method thereof

Abstract

The present invention relates to a cell line of lymphocytes comprising γδ T cells, composition and production method thereof, and medical use namely for the use in medicine, namely in cancer immunotherapy.The cell line comprise a sample of human peripheral blood Vδ1+γδ T cells expressing functional natural cytotoxicity receptors (NCRs). These Vδ1+ NCR+ T lymphocytes can directly mediate killing of leukemia cell lines and chronic lymphocytic leukemia patient neoplastic cells.The present invention shows that human Vδ1+ NCR+ T cells can be differentiated and expanded from total γδ peripheral blood lymphocytes (PBLs), upon regular in vitro or ex vivo stimulation with γδTCR agonists and γc-family cytokines. This subset surprisingly expresses NKp30, NKp44 and NKp46, and high levels of Granzyme B that associate with highly enhanced cytotoxicity against lymphoid leukemias.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The invention relates to a cell line of lymphocytes comprising γδ T cells, composition and production method thereof, and medical use namely for the use in medicine, namely in cancer immunotherapy.BACKGROUND[0002]Tumors develop in hosts endowed with a highly complex immune system that includes various lymphocyte subsets capable of recognizing and destroying transformed cells. It is now widely accepted that, while lymphocytes may constantly patrol tumor formation, cancer cells develop molecular strategies to evade immune surveillance, which are competitively selected under the pressure of the host immune system. This dynamic process, termed “cancer immunoediting”, is thought to constitute a major obstacle to cancer immunotherapy.[0003]Among multiple immune evasion mechanisms, it was recently shown that leukemia and lymphoma primary samples often down-regulate the non-classical MHC (major histocompatibility complex) protein, ULBP1, which is critic...

AI Technical Summary

Benefits of technology

The present invention relates to a cell line of peripheral blood lymphocytes expressing natural cytotoxicity receptors (NCR) and more specifically, the cell line consists of Vδ1+γδ PBL cells expressing functional natural cytotoxicity receptors, namely NKp30. The cell line can also contain other subsets of cells such as Vδ2+γδ PBL cells or cells expressing granzime B. The cell line can be used in medicine for the treatment of viral infections, tumors, or cancers, among others. The invention also includes a method of cultivating the cell line in the presence of γδTCR agonists and γc-cytokines. The γδTCR agonists and γc-cytokines can be added to the culture until at least 40% of the cells express natural cytotoxicity receptors, more preferably at least 50%, 60%, 70%, 75%, 80%, 85%, 95%, or 100%. The γδTCR agonist can be any soluble or immobilized molecule or compound that activates, stimulates, or triggers the γδTCR / CD3 receptor complex expressed in all Vδ1+γδ PBL, including plant lectins, anti-CD3 monoclonal antibodies, or other agonistic antibodies to the Vδ1+γδTCR.

Problems solved by technology

This dynamic process, termed “cancer immunoediting”, is thought to constitute a major obstacle to cancer immunotherapy.

Furthermore, clinical trials involving the in vivo administration of activators of Vγ9Vδ2 T-cells have shown limited success, with objective responses restricted to 10-33% of patients with either hematological or solid tumors.

This likely constitutes an important limitation to current γδ-T-cell-mediated immunotherapy.

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